Multiple sclerosis (MS) is a common inflammatory disorder of the central nervous system characterized by a complex etiology that includes a strong genetic component. Identification of the major genes that confer susceptibility to MS is now possible as a result of the rapid progress in delineating the extent of genetic variation across the human species. Emerging evidence indicates that the human genome retains blocks (haplotypes) of varying size (averaging 20-30kappaB) in which genes are held together in linkage disequilibrium (LD). These blocks define genomic segments of sequence unbroken by recombination in modern evolution, allowing for the efficient testing of all genetic variation within a region regardless of whether all variants have been discovered. A haplotype-map approach can now be used to finely map the regions of genetic interest. In specific aim 1 we describe the haplotype-based association analysis for the final identification of the causal variation(s) within the 4 MB major histocompatibility complex (MHC) locus at 6p21. This locus represents the strongest and most consistent genetic factor identified in MS. A robust haplotype-map of this region is already available. The haplotype-tagged (ht) SNPs will be genotyped in 1000 MS trios. Family-based association testing for alleles, haplotypes and genotypes in each block will be performed using transmission disequilibrium testing methods. MS susceptibility genes located within blocks of interest will then be identified by direct sequencing. In the second aim, we will address the issue of genetic modifiers in MS focusing first on the underlying causes of optico-spinal MS. Clinical and laboratory data such as age and site of disease onset, disability at entry of study (EDSS), lesion distribution, progression, and presence of autoantibodies will be also incorporated into the analysis of genomic data to directly address the question of heterogeneity in MS by analysis of the correlation between different phenotypes and genotypes. Based on the hypothesis that MS encompasses more than one fundamental phenotype, a genetic approach using family-based association studies was designed to identify genetic factors affecting disease pathogenesis. Key to the success of these studies is the availability of a large and informative dataset, the standardization of rigorous and consistent methods to collect relevant clinical data as stratifying variables for genetic analyses, and the application of efficient methods of genotyping and statistical analysis. Collaborative ties with skillful teams, access to a formidable DNA collection, a superb research environment and suggestive preliminary results, all indicate that this project has a high chance for success.